DESCRIPTION (Applicant's Abstract): The primary goal of this project is to develop novel and useful drugs for the control of pain and drug abuse. Recent years have seen a resurgence of opioid abuse, as well as the need for additional analgesics with limited abuse potential. Our objectives are to identify new receptor targets and lead drug candidates for further development. The project contains three major aims. The first focuses on heroin and morphine-6beta-glucuronide. Recent work indicates that these two agents act through a common receptor which is distinct from the mu receptor mediating morphine analgesia. The first aim will explore the structure-activity relationships of both agonists and antagonists selective for this receptor based upon several lead compounds which we have identified. The second aim addresses the role of the anti-opioid sigma1 receptor system in the modulation of opioid analgesia. Sigma1 agonists potently reverse the analgesic activity of a variety of classes of opioid analgesics while sigma1 antagonists potentiate opioid analgesia. The sigma1 receptor has recently been cloned and will serve as a basis for examining this system at the molecular level. The cloned receptor also can serve as a screening system for potential new drugs. The last aim involves further studies with a series of opioid analogs synthesized in the laboratory during the previous granting period. The recent identification of orphanin FQ/nociceptin (OFQ/N) has opened a new area of investigation. In addition to the major OFQ/N receptor, detailed binding studies have identified another subtype which binds traditional opiates quite poorly. However, we have identified an opioid derivative which labels this site with high affinity (Ki <5 nM) and which will serve as a lead compound in the design of more potent and selective alkaloid agonists and antagonists for this site. Finally, we will continue our efforts to synthesize radiolabeled affinity labels.